There is an emerging threat of the use of respiratory pathogens as weapons of bioterrorism. Thus it is imperative that we understand the interaction of viral pathogens with the immune response in the specialized microenvironment of the lung. Although a number of pathogens pose a threat, of particular concern is variola virus. Infection with variola virus results not only in significant morbidity, but in significant fatality. As a result of the eradication of smallpox, the vaccine was discontinued in 1972, leaving those under the age of 30 unprotected. In addition there is significant concern regarding the length of time protection is sustained following immunization, such that older individuals are also likely to be susceptible to infection and disease. Surprisingly in spite of the development of an effective vaccine for variola virus, many questions remain in our basic understanding of the interaction of this virus with the host immune response. We have developed a model for respiratory infection with vaccinia virus, the closely related virus used in the vaccine against smallpox. An advantage of the studies in this application is that they focus on the immune response following intranasal infection, a natural route by which variola virus is obtained and a likely route of inoculation for agents of bioterrorism. The studies in this application build on our published novel observation that the CD8 + T cell response following intranasal infection of mice with a high dose of vaccinia virus is severely decreased compared to mice receiving 100-fold less virus. The goal of the studies proposed herein is the identification of the mechanism(s) responsible for the decreased T cell response. In aim 1 we will determine whether the reduced response following high dose infection is the result of the inefficient activation/expansion of cells or whether anergy and/or apoptosis is induced in responding CD8 [unreadable] T cells. In aims 2 and 3 respectively, the contribution of the antigen presenting cell and the innate/inflammatory response in the lung to the reduced CD8 [unreadable] T cell response observed following high dose infection will be evaluated. The results from these studies will provide new and important information on the negative regulation of the immune response following respiratory infection and may lead to the development of novel therapeutics that can be used to boost the immune response following respiratory infection with viruses.